Emilio Poggio, M.D., the applicant for this K23 application, has completed clinical training in Nephrology at the Cleveland Clinic Foundation and has spent three years as a research fellow in the laboratory of Peter S. Heeger, M.D. The proposed 5-year training program, which includes didactic coursework and practical human investigation, is designed to allow Dr. Poggio to develop a career in patient-oriented research under the continued supervision of Dr. Heeger, with the ultimate goal of becoming an independent clinician investigator. Dr. Heeger is a pioneer in the development and application of immune monitoring techniques, including adapting the ELISPOT assay for clinical use in human transplantation, and has significant mentoring experience. The overall goal of the research plan is to evaluate the impact of preexisting effector/memory alloreactive T cells on post-transplant outcome in humans. Despite significant advances in immunosuppression and in the general care of transplant patients, the long-term outcome of renal allografts remains unsatisfactory as many grafts are lost in part due to immune-mediated injury. Circulating alloreactive memory/effector T cells are detectable in humans prior to transplantation, and are capable of rapidly engaging effector functions upon reexposure to their specific antigen. Based on strong preliminary data, we hypothesize that alloreactive effector/memory T cells existing before transplantation will independently and negatively impact on post-transplant outcome. To test this hypothesis we propose the 2 specific aims: 1) To characterize pre-transplant alloreactive effector/memory T cell immunity in kidney transplant candidates, and 2) To evaluate the relationship between pre-transplant cellular alloimmunity with post-transplant outcomes. In addition to providing insight into the role of effector/memory alloreactive T cells in human renal allograft recipients, our studies will assess the clinical utility of the alloreactive interferon gamma ELISPOT assay (and the Panel of Reactive T Cells or PRT) as an immune monitoring tool in humans, an approach that has enormous potential for affecting clinical care. As Dr. Poggio gains experience and independence, he plans to use the findings derived from this work to design clinical trials aimed at individualizing therapy and to potentially limit drug toxicity, thereby enhancing long-term graft function and prolonging graft survival. [unreadable] [unreadable] [unreadable] [unreadable]